1-235380161-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG-TTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_003193.5(TBCE):c.100+62_100+65dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

TBCE
NM_003193.5 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.401

Publications

1 publications found

Variant links:

Genes affected

TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

TBCE Gene-Disease associations (from GenCC):

hypoparathyroidism-retardation-dysmorphism syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
encephalopathy, progressive, with amyotrophy and optic atrophy
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
autosomal recessive Kenny-Caffey syndrome
Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

TBCE links:

ENSG00000285053 (HGNC:):

ENSG00000285053 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 1-235380161-T-TTGTG is Benign according to our data. Variant chr1-235380161-T-TTGTG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 296290.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00101 (142/139956) while in subpopulation AMR AF = 0.00177 (24/13522). AF 95% confidence interval is 0.00122. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TBCE	NM_003193.5 link	c.100+62_100+65dupGTGT	intron_variant	Intron 2 of 16	ENST00000642610.2	NP_003184.1	Q15813-1
TBCE	NM_001287801.2 link	c.100+62_100+65dupGTGT	intron_variant	Intron 2 of 17		NP_001274730.1	Q15813-2
TBCE	NM_001079515.3 link	c.100+62_100+65dupGTGT	intron_variant	Intron 2 of 16		NP_001072983.1
TBCE	NM_001287802.2 link	c.-211+62_-211+65dupGTGT	intron_variant	Intron 2 of 15		NP_001274731.1	Q15813A0A2R8Y6Q1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBCE	ENST00000642610.2 link	c.100+12_100+13insTGTG		intron_variant	Intron 2 of 16		NM_003193.5	ENSP00000494796.1		Q15813-1
ENSG00000285053	ENST00000647186.1 link	c.100+12_100+13insTGTG		intron_variant	Intron 4 of 18			ENSP00000494775.1		Q15813-1

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

142

AN:

139834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000471

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00178

Gnomad ASJ

AF:

0.00694

Gnomad EAS

AF:

0.000631

Gnomad SAS

AF:

0.000733

Gnomad FIN

AF:

0.000599

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000349

AC:

349

AN:

998736

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

189

AN XY:

511986

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25166

American (AMR)

AF:

0.000625

AC:

AN:

41592

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

21122

East Asian (EAS)

AF:

0.000441

AC:

AN:

34030

South Asian (SAS)

AF:

0.000401

AC:

AN:

74834

European-Finnish (FIN)

AF:

0.000280

AC:

AN:

46510

Middle Eastern (MID)

AF:

0.000222

AC:

AN:

4512

European-Non Finnish (NFE)

AF:

0.000276

AC:

195

AN:

707610

Other (OTH)

AF:

0.000438

AC:

AN:

43360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.321

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00101

AC:

142

AN:

139956

Hom.:

Cov.:

AF XY:

0.000938

AC XY:

AN XY:

67134

show subpopulations

African (AFR)

AF:

0.000469

AC:

AN:

38366

American (AMR)

AF:

0.00177

AC:

AN:

13522

Ashkenazi Jewish (ASJ)

AF:

0.00694

AC:

AN:

3314

East Asian (EAS)

AF:

0.000632

AC:

AN:

4748

South Asian (SAS)

AF:

0.000734

AC:

AN:

4088

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

8350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00102

AC:

AN:

64506

Other (OTH)

AF:

0.00

AC:

AN:

1906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypoparathyroidism-retardation-dysmorphism syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over